1-(2-ethyl-6-methylphenyl)-3-(2-hydroxy-4-nitrophenyl)urea | 1202526-46-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 1-(2-ethyl-6-methylphenyl)-3-(2-hydroxy-4-nitrophenyl)urea
• CAS: 1202526-46-2
• 化学式: C₁₆H₁₇N₃O₄
• 分子量: 315.329
• InChiKey: OCNYLKSGSLFCSE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  107
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  异氰酸2-乙基-6-甲基苯酯 、 2-氨基-5-硝基苯酚 以 四氢呋喃 为溶剂， 反应 12.0h， 以42%的产率得到1-(2-ethyl-6-methylphenyl)-3-(2-hydroxy-4-nitrophenyl)urea
  参考文献：
  名称：

  Structural optimization of a CXCR2-directed antagonist that indirectly inhibits γ-secretase and reduces Aβ

  摘要：

  Amyloid beta(A beta), a key molecule in the pathogenesis of Alzheimer's disease (AD), is derived from the amyloid precursor protein (APP) by sequential proteolysis via beta- and gamma-secretases. Because of their role in generation of A beta, these enzymes have emerged as important therapeutic targets for AD. In the case of gamma-secretase, progress has been made towards designing potent inhibitors with suitable pharmacological profiles. Direct gamma-secretase inhibitors are being evaluated in clinical trials and new strategies are being explored to block gamma-secretase activity indirectly as well. In this regard, we have previously reported an indirect regulation of gamma-secretase through antagonism of CXCR2, a G-protein coupled receptor (GPCR). We demonstrated that N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea (SB225002), a selective inhibitor of CXCR2 also plays a role in an indirect inhibition of gamma-secretase. Furthermore, we reported a similar to 5-fold difference in the selective inhibition of APP versus Notch processing via gamma-secretase following treatment with SB225002. Herein we describe the synthesis and optimization of SB225002. By determination of the structure-activity relationship (SAR), we derived small molecules that inhibit A beta 40 production with IC(50) values in the sub-micromolar range in a cell-based assay and also validated the potential of CXCR2 as a new target for therapeutic intervention in AD. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.09.051

文献信息

• Structural optimization of a CXCR2-directed antagonist that indirectly inhibits γ-secretase and reduces Aβ
  作者：Pancham Bakshi、Chao Jin、Pierre Broutin、Beniam Berhane、Jon Reed、Michael Mullan

  DOI：10.1016/j.bmc.2009.09.051

  日期：2009.12

  Amyloid beta(A beta), a key molecule in the pathogenesis of Alzheimer's disease (AD), is derived from the amyloid precursor protein (APP) by sequential proteolysis via beta- and gamma-secretases. Because of their role in generation of A beta, these enzymes have emerged as important therapeutic targets for AD. In the case of gamma-secretase, progress has been made towards designing potent inhibitors with suitable pharmacological profiles. Direct gamma-secretase inhibitors are being evaluated in clinical trials and new strategies are being explored to block gamma-secretase activity indirectly as well. In this regard, we have previously reported an indirect regulation of gamma-secretase through antagonism of CXCR2, a G-protein coupled receptor (GPCR). We demonstrated that N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea (SB225002), a selective inhibitor of CXCR2 also plays a role in an indirect inhibition of gamma-secretase. Furthermore, we reported a similar to 5-fold difference in the selective inhibition of APP versus Notch processing via gamma-secretase following treatment with SB225002. Herein we describe the synthesis and optimization of SB225002. By determination of the structure-activity relationship (SAR), we derived small molecules that inhibit A beta 40 production with IC(50) values in the sub-micromolar range in a cell-based assay and also validated the potential of CXCR2 as a new target for therapeutic intervention in AD. (C) 2009 Elsevier Ltd. All rights reserved.